Various patents, patent publications and scientific articles may be referred to throughout the specification. The contents of each of these documents are incorporated by reference herein, in their entireties.
Natural pulmonary surfactants (PS) are protein/lipid compositions that are produced naturally in the lungs and are critical to the lungs' ability to absorb oxygen. They cover the entire alveolar surface of the lungs and the terminal conducting airways leading to the alveoli. Surfactants facilitate respiration by continually modifying the surface tension of the fluid normally present within the alveoli. In the absence of sufficient surfactant, or should the surfactant degrade, the alveoli tend to collapse and the lungs do not absorb sufficient oxygen. By lowering the surface tension of the terminal conducting airways, surfactant maintains patency, i.e., keeps airways open. Loss of patency leads to loss of patency obstruction of the airway and compromised pulmonary function. Human surfactants primarily contain: phospholipids, the major one being dipalmitoyl phosphatidyl-choline (DPPC), and four surfactant polypeptides, A, B, C and D with surfactant protein B (SP-B) being the most essential for respiratory function. Natural and synthetic pulmonary surfactants are commonly used to treat respiratory distress syndrome in premature infants shortly after birth.
Bronchopulmonary dysplasia (BPD or BD), also referred to as chronic lung disease (CLD), is a common, occasionally life threatening, lung disease typically occurring in premature infants who survive respiratory distress syndrome (RDS) and other complications of prematurity. With the near universal adoption of antenatal steroids and post-natal use of exogenous lung surfactants, large numbers of at-risk low birth weight infants now survive the acute lung disease of prematurity only to develop chronic lung disease. Prior to the widespread use of synthetic or animal derived surfactants, BPD was histologically characterized by airway injury and fibrosis. Since the advent of surfactant replacement therapy, infants appear to experience less airway and fibrotic involvement than described in earlier reports but have abnormalities in alveolarization and vascularization. The change in the nature of the condition has led neonatologists to refer to a “new BPD”. BPD can also develop in term infants who require respiratory support at birth or soon thereafter.
Surfactant therapy has decreased the frequency with which larger, moderately premature infants develop the disease, but the survival benefits of surfactant in extremely premature infants has resulted in a shift in the incidence of BPD toward smaller, more premature babies. Post-natal steroids in anti-inflammatory doses are known to modestly decrease the physiologic consequences of BPD, but at the expense of neuro-developmental outcomes. Further, steroids may decrease alveolarization. Vitamin A derivatives stimulate alveolarization in animals, but clinical results have been modest. Despite an intriguing rationale, antioxidants have proven to be of little value. Whether inhaled nitric oxide will decrease the likelihood of BPD in very low birth weight infants awaits the outcome of ongoing clinical trials.
Causes of BPD or CLD are probably multi-factorial. However, the pathophysiologic antecedents and consequences of BPD may suggest a new approach to prevention with drugs already in clinical use. Decreased lung compliance as a consequence of initially mild pulmonary edema has been shown to correlate with subsequent development of BPD. Neutrophil migration to the lung increases in the presence of pulmonary edema and hyperoxia. When these cells are activated, they release proteases and inflammatory mediators including oxidants that can further injure the lung. These events degrade pulmonary function necessitating mechanical ventilation for many infants initially weaned from the ventilator and increasing ventilator requirements for those never able to wean. Surfactant is itself a target of proteases, oxidant species and small molecule mediators and can be inactivated by many plasma proteins found in bronchoalveolar fluid in the presence of capillary leak.
Treatments to prevent or ameliorate BPD and related pulmonary disorders are needed. The present invention is directed to this and other important needs.